Cue Biopharma, Inc.

Good afternoon, ladies and gentlemen, and welcome to the CUBE Biopharma third quarter 2023 earnings call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question and answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. As a reminder, this call is being recorded today, Thursday, November 9, 2023. I would now like to turn over the conference to Dan Passeri, Chief Executive Officer. Please go ahead.

Yeah, thank you, and good afternoon, everyone. As a reminder, this presentation and discussion is being recorded and will be available on our website for the next 30 days. Also be aware that the slides accompanying today's update may be advanced directly by those listening in on the call, and we'll notify you of what slide we're on throughout the presentation. Joining me on today's call is Dr. Anish Suri, our President, Chief Scientific Officer, Dr. Matteo Levesetti, our Chief Medical Officer, and Kerry Ann Millar, our Chief Financial Officer. As shown on slide number two, the presentation and overview may contain some forward-looking statements, and any forward-looking statement made during this call represents the company's views only as of today, November 9th, 2023. The next slide, slide number three, outlines the agenda for today's call, and I'll begin with a brief summary overview of our therapeutic platform and core competitive positioning, which is bolstered and further validated by the recent data update presented this past weekend at CITSE. I'll then turn the call over to Matteo, who will provide a detailed synopsis of our clinical data from both the monotherapy and combination portions of the ongoing Q101 trial. as well as the highly encouraging early signs of clinical activity from the dose escalation portion of the Q102 monotherapy trial. As a reminder, these data are representative of our modular immunostat platform, which we believe has significant potential for broad market applications in cancer immunotherapy, autoimmune and inflammatory diseases, as well as chronic infectious diseases. After Matteo, Anish will provide further details of our platform developments, underscoring the far-reaching potential of our approach for selective modulation of disease-specific T cells and the potential for superior differentiation. Following Anish, Kerry will provide an overview of our financials for Q3 and guidance going forward. I'll then return for some concluding remarks and open the call for questions. All right, let me first begin by emphasizing our strategic positioning and core competitive advantages. It's self-evident that within the immuno-oncology sector, there have been significant and persistent challenges and realizing the fullest potential of immunotherapies. While many therapeutic modalities and combination approaches for immune modulation are being pursued, significant challenges exist with respect to suboptimal efficacy the safety and tolerability experienced by patients, scalability and cost of goods to enable broad patient reach. It's important to note that despite the significant promise of checkpoint inhibition, such as anti-PD-1, PD-L1 antibodies, there remains a pressing unmet medical need within oncology for an effective and well-tolerated means of stimulating and activating relevant anti-cancer T-cells while sparing the vast majority of cancer-irrelevant T cells. Solution providers to these challenges will likely emerge as best-in-class market leaders defining the paths forward for more effective therapeutics, both as standalone treatment options as well as combination approaches, for example, with checkpoint inhibitors. To that end, As shown in slide four, we believe our Immunostat platform offers a potential breakthrough path forward for cancer immunotherapy. With data from over 100 cancer patients dosed with Immunostats from our IL-2-based Q100 series, and namely that's the experience with Q101 targeting HPV E7 and Q102 targeting Wilms Tumor 1, We can summarize some key distinguishing features bolstering our competitive positioning in this crowded space. There are four predominant and core features to highlight. First, as noted in this slide, we have created a therapeutic index for IL-2 by selectively targeting tumor-specific T cells through the T cell receptor, or TCR, that provides the highest degree of specificity for the desired T cells relevant to anti-tumor immunity. When we refer to a therapeutic index, this basically refers to the ability to dose patients at a range of doses whereby they experience demonstrable clinical benefit, example, an increase in overall response rate and or an increase in median overall survival, while also having an accepted tolerability profile for maintaining quality of life. There have been high-profile field approaches attempting to develop IL-2 therapies for cancers. Notable among these recent failures are pegylated versions of IL-2 and not alpha variants of IL-2. There have also been failures in combinations with pembrolizumab with, for instance, kinase inhibitors where they may have an ORR but a very poor tolerability profile. Our success with IL-2 may also be replicated For many other cytokines and immune-activating receptors, where the generation of a therapeutic index would be of paramount importance to maximize efficacy while preserving patient safety and tolerability. Second, our clinical candidates demonstrate anti-tumor efficacy in late-stage poor prognosis refractory metastatic cancer patients, both as monotherapy and in combination with checkpoint inhibitors, namely pembrolizumab anti-PD-1 antibody. While much of the maturing efficacy data is from our Q101 trial in HPV-positive refractory and metastatic head and neck squamous cell carcinoma patients, we have also begun to observe antitumor activity with our second clinical candidate, Q102, that is currently in the dose escalation portion of a monotherapy trial in patients suffering from metastatic solid metastasis. cancers, namely colorectal cancer, ovarian, pancreatic, and gastric cancer. These WT1 overexpressing cancers have historically not been responsive to checkpoint inhibitor therapy and have a poor prognosis. Hence, demonstrating disease control and antitumor activity may represent a breakthrough that can be further expanded with checkpoint inhibition and our other combinations to benefit these patients in need of new therapeutic options. Matteo will present and discuss these clinical data in greater detail in a moment. Third point, we believe that maturing clinical data from the Q101 trial offers opportunities to pursue multiple registrational paths in HPV-positive refractory metastatic head and neck patients. They prolong survival signal that we've seen in the Q101 monotherapy treatment arm and second line and beyond patients. In fact, the majority of the patients are beyond third line. And the enhanced overall response rate with maturing progression-free survival and overall survival in frontline patients treated with Q101 and standard of care pembrolizumab offer attractive development opportunities in these respective lines of treatment. To that end, we have submitted a request for discussions and feedback from the FDA to gain alignment and clarity on the next steps towards a registrational trial. Importantly, Q101 serves as a clinical validation beachhead from which we can expand the application of the Q100 series across many different cancers. A key strength of our platform is the modularity wherein any given tumor antigen can be incorporated to selectively activate the relevant cancer-specific T cells. This strategy has also significant regulatory advantages since the core IL-2 framework, which has been de-risked by Q101, remains essentially the same across therapeutic molecules of the Q100 series. And this was clearly demonstrated with the IND approval of our second clinical candidate, Q102. In essence, the IND application for 102 was supported by the clinical data from Q101 as an analog molecule, where the FDA did not require us to perform additional IND-enabling preclinical toxicology studies, and we were allowed to initiate the Q102 clinical trial at an active dose of one mg per kg, which is essentially a situation that saved us about a year in dose escalation timelines and the associated costs And these will provide additional details on our focus strategy of expanding our preclinical pipeline with validated immunostats targeting attractive tumor antigens, such as KRAS, involving the G12 hotspot mutations and other tumor antigens. As conveyed in this slide, we believe we are positioned as a potential leading solution provider, realizing the promise of precision immune modulation for superior patient outcomes. As such, we believe Our data places us in a potential position as not only first-in-class for selective modulation of disease-relevant T cells, but also best-in-class therapeutic platform for immunotherapy. With that background on the progress in differentiation and competitive positioning, I'm going to turn the call over to Matteo to review the clinical data, particularly what we just presented at CISI. Matteo?

Thanks, Dan. Good afternoon to everyone listening in on today's call. I am particularly pleased to provide you with this summary update as the clinical data from the ongoing Q101 trial continues to demonstrate highly encouraging and robust metrics of clinical benefit for heavily pretreated recurrent metastatic HPV positive head and neck cancer patients treated with monotherapy and for newly diagnosed patients with recurrent HPV positive head and neck squamous cell carcinoma treated in combination with Pembrolizumab. As shown on slide five, data from the ongoing clinical trials with Q101 as monotherapy and in combination with Pembrolizumab have provided clinical proof of concept and de-risking of our Immunostat platform. The latest data generated to date in 2023 continues to support prior observations and further enhances our confidence in Q101. as a potential therapeutic for patients battling HPV-positive head and neck cancer. As previously and consistently stated, we believe Q101's mechanism of action, as evidenced by the ongoing data generated to date, provides effective and tolerated dose levels, enabling selective expansion of targeted tumor-specific T cells. Recurrent metastatic HPV-positive head and neck cancer is a tough and curable disease. we have observed throughout the monotherapy trial bolsters our position and enhances our confidence that Q101 is in fact stimulating the targeted cancer-specific T cells within these patients resulting in demonstrable anti-tumor effect. Furthermore, and importantly, we continue to observe an evolving pattern of disease control and enhanced survival in the monotherapy trial. We believe this enhanced survival is due to the superior qualitative features of tumor-specific T cells given Q101's mechanism of action, especially in the tumor microenvironment, and the recent description of the role of IL-2 in generating potent effector CD8-positive T cells. On this note, enrollment in the neoadjuvant trial is progressing well, and preliminary observations demonstrate expansion of T cell clonality and increases in natural killer cells within the tumor microenvironment. These findings are consistent with the pharmacodynamic changes observed in the peripheral blood of patients treated with Q101 as previously reported. We believe these observations, in addition to the clinical efficacy observed in the second and first line recurrent metastatic setting, support a development strategy of moving further upstream into earlier lines of therapy where a larger number of patients may benefit. We believe the selective perturbation of the relevant immune cells results in durable clinical benefit as seen in Q101 treated patients that have failed prior checkpoint inhibitor treatment. As shown on slide six, durable clinical responses are observed with Q101 monotherapy. Now with new data demonstrating an unconfirmed partial response in a patient at 24 months after starting therapy. As shown before, patient A experienced a durable partial response with an approximate 60% reduction in tumor burden evident at six weeks after the first two cycles of Q101, which lasted close to one year on therapy. Importantly, this patient also demonstrated a significant reduction in HPV cell-free DNA that coincided with the initiation of the partial response, and HPV cell-free DNA remained undetectable for the majority of time on treatment. Patient B, who just completed 24 months of treatment, has demonstrated an unconfirmed partial response on their Cycle 35 scan. Notably, this patient has also had complete disappearance of HPV cell-free DNA in the blood since week six. The undetectable HPV cell-free DNA, which is an increasingly recognized biomarker of disease activity, is suggestive of a pathologic complete response or cure in this patient who we expect may have surgical resection of the lesion for histopathological analysis. As shown on slide seven, the current Kaplan-Meier estimate of median overall survival observed in the 20 patients treated that the recommended phase two dose of four milligrams per kilogram is 20.8 months. The observed median overall survival of greater than 20 months in patients treated in the third line and beyond is notable when compared to the historical median overall survival of approximately eight months observed in patients treated in the second line in the Checkmate 141 and Keynote 40 trials of nivolumab and pembrolizumab, respectively. As any experienced oncologist understands, the survival with third line treatment is expected to be less as the disease has further developed and become more unstable. Our evolving data continues to support the premise that treatment with Q101 demonstrates single agent activity by durably expanding tumor-specific T cells with anti-tumor activity, resulting in what appears to be a meaningful increase in survival for patients with advanced recurrent metastatic HPV-positive head and neck cancer. Based upon the strength of this data, we plan to meet with FDA to define a registration path for Q101. The demonstration of monotherapy activity in these patients bolsters our belief that we should observe complementary mechanistic effects in combination with pembrolizumab, As indicated on slide 8, I will now provide an update on the ongoing trial of Q101 in combination with pembrolizumab in first-line recurrent metastatic HPV-positive head and neck cancer patients. Pembrolizumab is approved for the treatment of first-line patients with recurrent metastatic head and neck cancers that have tumors with complete positivity scores greater than or equal to 1%. which is an equal, which is a measure of PD-L1 expression. The next slide, slide 9, shows the current overall response rate of 47% observed in first-line patients treated with Q101 and pembrolizumab as presented at the CITC meeting earlier this month. The overall response rate of 47% observed in patients with CPS scores greater than or equal to 1 treated with Q101 in combination with pembrolizumab to date represents a greater than doubling compared to the historical overall response rate of 19% observed with pembrolizumab monotherapy in the Keynote 48 study. Notably, for patients with CPS scores of 1 to 19, an overall response rate of 56% was observed with Q101 and pembrolizumab, which represents a greater than tripling of the historical overall response rate of approximately 15% observed with pembrolizumab alone. Furthermore, Q101 also appears to increase the overall response rate in patients with CPS scores greater than 20, with an overall response rate of 38% for Q101 and pembrolizumab and an overall response rate of 23% for pembrolizumab alone. In totality, our data suggests that not only does Q101 appear to demonstrably enhance the response rate of anti-PD-1 inhibition, but also does so by substantially expanding responses in patients that are traditionally less likely to respond. This is particularly important since patients with low CPS scores, range of 1 to 19, represent approximately 50% of all patients that are CPS positive and eligible for treatment with checkpoint inhibitor in the frontline setting. The swimmer plot shown on slide 10 shows that 21 of the 22 patients treated to date at the RP2D in the ongoing combination trial of Q101 remain alive as of the last follow-up for each patient. Of note, the median progression-free survival is still maturing and is currently at 5.8 months, which compares favorably to the historical median progression-free survival of 3.2 months observed with pembrolizumab monotherapy in the Keynote 48 trial. Eight patients have lived beyond 12 months, which was the median overall survival observed in patients treated with pembrolizumab alone in the Keynote 48 study. A summary of the clinical validation and platform de-risking of immunostats via the Q101 clinical experience is shown on slide 11. Key observations in patients treated with Q101 monotherapy in the third line and beyond include demonstration of single-agent antitumor efficacy evidenced by resist-based partial response, and durable stable disease in third-line and beyond recurrent metastatic cancer patients, and a median overall survival of greater than 20 months in the recommended phase 2 dose cohort. In the first-line setting, Q101 and pembrolizumab demonstrates an objective response rate of 47% and a current median PFS of close to six months, which is continuing to mature As previously announced, the robust data on Q101's activity in monotherapy and in combination with pembrolizumab enabled the granting of PRESS fast-track designation for the treatment of patients in both the first and third line setting. The fast-track designation will facilitate planned interactions with the FDA to define a monotherapy registration path. The cumulative data from these ongoing trials with Q101 have provided us with clear evidence of targeted expansion of HPV E7-specific T cells with anti-tumor activity as a single agent and as a complementary mechanism with checkpoint inhibition for what we believe will broaden patient reach and enhance efficacy of checkpoint blockade therapy. Furthermore, we believe the preliminary observations from the neoadjuvant study in addition to the clinical efficacy observed in the second and first line recurrent metastatic setting, support a development strategy of moving further upstream to earlier lines of therapy where a larger number of patients may benefit. As such, we believe Q101, our first biologic therapeutic from our Q100 series, represents a potential therapeutic breakthrough for patients. Moreover, we believe the data from Q101 has provided a de-risking and mechanistic validation for additional biologics from the IL-2-based Q100 series, beginning with Q102. As a reminder, shown on slide 12, Q102 and Q101 share 99% amino acid sequence identity. This enabled us to significantly decrease the development time and cost of Q102, as we're not required by the FDA to repeat IND-enabling toxicology studies for Q102, And we are also able to initiate the phase one dose escalation study at one milligram per kilogram, a dose at which we observe clear signs of biologic activity with Q101. As shown on slide 13, we are conducting the Q102 dose escalation study in colon, gastric, pancreatic, and ovarian cancers. This design offers us the ability to perform monotherapy expansion studies in any for all of the indications being evaluated in the dose escalation phase of the trial. The study is actively enrolling patients in all four indications. The patient screening and enrollment rate continue to go exceedingly well, underscoring investigator enthusiasm and the need for effective therapies in WT1-positive cancers. We have observed substantial WT1 expression across the target indications. with 60% of colorectal, 53% of gastric, 100% of ovarian, and 60% of pancreatic cancers testing positive. We have completed enrollment of patients in cohort four at a dose of eight milligrams per kilogram and are expanding the two and four milligram cohorts. Q102 has been well tolerated to date with no dose limiting toxicity observed. The expansion of cohorts two and three will provide additional pharmacokinetic, pharmacodynamic, and antitumor activity data to help inform the selection of the recommended phase 2 dose for the expansion cohorts. Data on the first 18 dose escalation patients treated with Q102 shown on slide 14 demonstrates encouraging disease control with rates of 80% and 75% observed in cohorts 2 and 3 respectively in this heavily pretreated patient population. Seven of the 11 patients treated in cohorts 2 and 3 remained on treatment at the time of data cutoff. Reductions in tumor burden have been observed in patients treated in the dose escalation portion of the study. As shown on slide 15, a patient with gastric cancer that progressed on three prior lines of therapy, including a checkpoint inhibitor, has experienced a decrease in the sum of three target lesions of minus 29% at week 24 and continues on treatment. Reductions of approximately minus 50% in the tumor markers CEA and CA19-9 coincide with the shrinkage of the patient's cancer. Another example of reduction in tumor burden observed in the two milligram per kilogram dose escalation cohort, this time in a patient with ovarian cancer, is shown on slide 16. This 52-year-old patient that progressed on four prior lines of therapy has experienced an unconfirmed partial response with a reduction of minus 30% in their tumor burden. We are encouraged by these early observations of monotherapy antitumor activity and these indications where checkpoint inhibitors have been largely ineffective. We look forward to presenting additional data at an upcoming scientific meeting. I will now turn the call over to Anish. Anish?